{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T23:16:39Z","timestamp":1789514199701,"version":"build-2803163510"},"reference-count":22,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2013,5,1]],"date-time":"2013-05-01T00:00:00Z","timestamp":1367366400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2013,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    High-throughput phenotypic screening against the yeast\n                    <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Saccharomyces cerevisiae<\/jats:named-content>\n                    revealed a series of triazolopyrimidine-sulfonamide compounds with broad-spectrum antifungal activity, no significant cytotoxicity, and low protein binding. To elucidate the target of this series, we have applied a chemogenomic profiling approach using the\n                    <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">S. cerevisiae<\/jats:named-content>\n                    deletion collection. All compounds of the series yielded highly similar profiles that suggested acetolactate synthase (Ilv2p, which catalyzes the first common step in branched-chain amino acid biosynthesis) as a possible target. The high correlation with profiles of known Ilv2p inhibitors like chlorimuron-ethyl provided further evidence for a similar mechanism of action. Genome-wide mutagenesis in\n                    <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">S. cerevisiae<\/jats:named-content>\n                    identified 13 resistant clones with 3 different mutations in the catalytic subunit of acetolactate synthase that also conferred cross-resistance to established Ilv2p inhibitors. Mapping of the mutations into the published Ilv2p crystal structure outlined the chlorimuron-ethyl binding cavity, and it was possible to dock the triazolopyrimidine-sulfonamide compound into this pocket\n                    <jats:italic>in silico<\/jats:italic>\n                    . However, fungal growth inhibition could be bypassed through supplementation with exogenous branched-chain amino acids or by the addition of serum to the medium in all of the fungal organisms tested except for\n                    <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Aspergillus fumigatus<\/jats:named-content>\n                    . Thus, these data support the identification of the triazolopyrimidine-sulfonamide compounds as inhibitors of acetolactate synthase but suggest that targeting may be compromised due to the possibility of nutrient bypass\n                    <jats:italic>in vivo<\/jats:italic>\n                    .\n                  <\/jats:p>","DOI":"10.1128\/aac.01809-12","type":"journal-article","created":{"date-parts":[[2013,3,11]],"date-time":"2013-03-11T21:07:32Z","timestamp":1363036052000},"page":"2272-2280","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":44,"title":["Identification and Evaluation of Novel Acetolactate Synthase Inhibitors as Antifungal Agents"],"prefix":"10.1128","volume":"57","author":[{"given":"Daryl L.","family":"Richie","sequence":"first","affiliation":[{"name":"Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine V.","family":"Thompson","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Studer","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivian C.","family":"Prindle","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Aust","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph","family":"Riedl","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Estoppey","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianshi","family":"Tao","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica A.","family":"Sexton","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Zabawa","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Drumm","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Cotesta","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00fcrg","family":"Eichenberger","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven","family":"Schuierer","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Hartmann","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N. 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